Oropharyngeal candidiasis (OPC) remains the most common oral manifestation of HIV infection. Although considerable progress has been made toward identifying the immunological events taking place at the oral mucosa that protects against, or contributes to, the development of clinical OPC, the underlying mechanisms or resistance and susceptibility to OPC remain poorly understood. Clinical and laboratory investigations suggest that Th1-type cell-mediated immunity by CD4+ T cells and related cytokines is the predominant host defense mechanism against oral C. albicans infection. Our data over the past 5 years supports this, but also adds considerable complexity. While OPC primarily occurs in those with reduced CD4 cell numbers, there is no evidence for a dysfunction in Candida-specific responsiveness by peripheral blood lymphocytes. Instead there appears to be a threshold number of CD4+ T cells required to protect the oral cavity against OPC, below which local mucosal mechanisms become increasingly critical. Accordingly, susceptibility to OPC during reduced CD4 cells correlates with a predominant Th2-type cytokine profile in saliva, an accumulation of CD8+ T cells that appear restricted from trafficking to the site of the superficial infection at the outer epithelium, and a reduced capacity for oral epithelial cells to inhibit the growth of C. albicans. Therefore, we hypothesize that CD8+ T cells and related cytokines/chemokines, together with epithelial cells, represent important oral host defense mechanisms when CD4+ T cells drop below protective levels and that dysfunctions in one or more of these defenses contribute to episodes of OPC. To test this hypothesis we w continue to focus on our large urban cohort of individuals with and without OPC in the HIV Outpatient Program at LSU Health Sciences Center and 1) evaluate the immune status of CD8+ T cells in oral tissue o HIV+ persons with and without OPC (longitudinal evaluation, adhesion molecules, activation/costimulation), 2) evaluate CD8+ T cell-associated cytokines/chemokines in oral tissues (protein and mRNA), and 3) identify the functional moiety and characterize the activity and mechanism of oral epithelial cell anti-Candida activity. The long-term goals of the project are to identify the specific immune factors associated with the susceptibility to OPC in HIV+ individuals, and to develop immunotherapeutic strategies to enhance resistance against OPC during periods of reduced CD4+ T cells.